No Slide TitleCollective Cell Migration
Min ZHAO Professor
Dermatology and Ophthalmology University of California Davis School of Medicine
Zhao (20 mins) MURI April 18 2018
“…conservative estimates for total Medicare annual spending for all wound types ranged from $28.1 billion to $31.7 billion” - Nussbaum et al., Value Health. 2018 Jan;21(1):27-32. doi: 10.1016/j.jval.2017.07.007. Epub 2017 Sep 19. An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds. 2014 data (Alliance of Wound Care Stakeholders)
https://en.wikipedia.org/wiki/Battlefield_ medicine
Not real, simulation
The Management of Combat Wounds: The British Military Experience. ADV. WOUND CARE, 2016, 5(10).
https://ispr.info/2012/10/25/simulated-wounds-prepare- combat-medics-for-real-thing/
Regeneration 100µm
– wound itself naturally produce electric fields Mechanical: stiffness and tension
Molecule signaling
how cells communicate within a group across all three BEM signaling modalities
50µm
Significantly scaling up in size and time 1. two order bigger in the size 2. From minutes to up to 20 hours and days in the time
From signaling event at molecular level to tissue behaviors
Electric field determines whether wounds close or open up.
Zhao …. Devreotes… et al., Nature. 2006. 442, 457-460.
Receptors
Directional Sensing
STEN –
CON
Aims of this part of MURI
• To understand how groups of cells sense and respond to electric stimuli
• To electrically coordinate multicellular functions
MURI team Wolfgang Losert (UMD), Quan Qing (ASU), Peter Devreotes (JHU)
Dr. Yaohui Sun
Volodymyr Ryzhuk, MSc
Dr. Yan Zhang
Liang Guo
Kan Zhu Morgan Trexler John Albeck Ahmed Hassan Cheng-Ming Chuong Robert Chow
Brian Reid
EF-regulated ERK activation and actin polymerization in epithelial cells
Qing Lab at ASU Advanced electrical stimulation device and application
Expanding and extending to Army Project (JAP, Dr. Trexler) Electrogenic biomaterials for severe cornea wounds
(DoD #W81XWH-14-1-0542) Other collective cell behaviors – NYU, USC, Oxford University (England)
Single cells
Large Protrusion
Time ( hour)
ERKTR ( a.u.)
DC electric fields activate ERK ERKTR ( a.u.) ERKTR ( a.u.) ERKTR ( a.u.)
ERKTR ( a.u.)
2. Cell sheets respond to EF by collective directional migration.
(with Pan lab at UC Davis)
7 hours
2, 00
0µ m
~8 -1
0 µm
/c el
l 25
0 X
2 50
Directional Sensing
STEN - CON
Devreotes slide
Cytoskeletal dynamics
Signaling dynamics
3. Cell sheets show “wave propagation” in migration directionality and speed similar to
“CON” and “STEN”. (Losert Group)
Quantitative analysis of Migration
5min 10min 15min 20min 25min 30min 35min 40m 45min 50min 55min 60min
NO EF
D ir
-1
1
0
EF on
Directional Sensing
4. Probing into the intracellular cytoskeletal networks signaling pathways (Quan Qing Lab, ASU; Losert Lab, MDU; Devreotes, JHU;
John Albeck lab, UC Davis)
Sebastian Losert Lab
Collective cell migration
t0
tn
ERK activation
Ve rti
Electrically regulated STEN- CON paradigm in collective cell migration.
1. Epithelial cells show similar response CON – cytoskeletal oscillation (membrane) STEN - signaling induced large protrusion.
2. Cell sheets respond to EF by collective directional migration, showing “wave propagation” in migration directionality and speed “CON” and “STEN”. (Losert group)
3. Probing into the intracellular signaling pathways (with ASU; MDU; JHU; John Albeck lab, UC Davis)
4. Collective sensing and responding – electrotaxis and chemotaxis (Mayor lab)
5. Collective cell migration in vivo (Chuong lab USC)
Current direction 1
To electrically control ERK activation
Amplitued modulation (AM) Frequency modulation (FM)
Quan Qing, ASU
Current direction 2
EF 4V/cm? New Paradigms -- STEN CON in collective migration
Single cell paradigms Multi-cell paradigms
Losert, MDU; Devreotes, JHU